1. Field of the Invention
The present invention relates to novel oligonucleotides, a pharmaceutical composition containing the oligonucleotide, and a method for inhibiting tissue fibrosis. The pharmaceutical composition of the present invention is useful for treating or preventing glomerulonephritis, glomerulosclerosis, interstitial fibrosis, pulmonary fibrosis, heart failure, cirrhosis, or angiitis.
2. Description of the Related Art
An extracellular matrix accumulation brings about glomerulosclerosis or interstitial fibrosis, which is a histological characteristic of progressive glomerular diseases, such as glomerulonephritis. The extracellular matrix forms a basement membrane or mesangial region of a glomerulus, and contains, for example, glycoproteins such as collagen, fibronectin, or laminin; or proteoglycans such as biglycan or decorin. The extracellular matrix regulates the functions of constituent cells in a normal glomerulus, but is increased upon the occurrence of glomerulonephritis or glomerulosclerosis, and is associated with a progress of nephritis.
According to recent findings, plasmin is known as one of the major factors regulating a turnover of the extracellular matrix in the mesangial cells. The formation of the plasmin is regulated by a balance between a plasminogen activator and various plasminogen activator inhibitors (PAIs). It is known that, in a glomerulus isolated from an animal model having proliferative glomerulonephritis, the accumulation of plasminogen activator inhibitor type 1 (PAI-1) to the extracellular matrix is increased. This suggests that PAI-1 is one of the key factors involved in the extracellular matrix accumulation in the mesangial cells. Namely, it is surmised that, when an amount of PAI-1 expressed is increased, the formation of plasmin, which is a protease, is inhibited, and as a result, the degradation of the extracellular matrix is inhibited. That is, it is surmised that, if the expression of PAI-1 can be inhibited, the extracellular matrix accumulation can be inhibited, and thus the tissue fibrosis can be prevented.
Therefore, it is expected that a compound capable of inhibiting the expression of PAI-1 is useful for treating or preventing diseases accompanied by an extracellular matrix deposition, such as glomerulonephritis, glomerulosclerosis, interstitial fibrosis, pulmonary fibrosis, heart failure, cirrhosis, or angiitis.
It is reported that each of angiotensin II and TGF-.beta. increases an expression of PAI-1 mRNA in specific cells by itself, respectively. Further, it is known that some compounds can inhibit the PAI-1 mRNA expression induced by an action of one of angiotensin II or TGF-.beta.. For example, Endocrinology, 130 (3), 1255-1262 (1992) discloses that angiotensin II increases the PAI-1 mRNA expression in an astroglia from a rat brain, and the induced expression of PAI-1 mRNA is inhibited by treating with a very high concentration of H-7, i.e., 1-(5-isoquinolinesulfonyl)-2-methylpiperazine, which is an inhibitor of protein kinase C. Further, Mol. Cell. Biol., 12 (1), 261-265 (1992) discloses that TGF-.beta.1 increases the PAI-1 mRNA expression in epithelial cells of an MvILu lung, and the induced expression of PAI-1 mRNA is inhibited by the above H-7. J. Clin. Invest., 95 (3), 1353-1362 (1995) discloses that angiotensin II increases the PAI-1 mRNA expression in rat aortic smooth muscle cells and vascular endothelial cells, and the induced expression of PAI-1 mRNA in the vascular endothelial cells is partially inhibited by a genistein, i.e., a tyrosine kinase inhibitor. Furthermore, Kidney Int., 51 (3), 664-671 (1997) discloses that angiotensin II increases the PAI-1 mRNA expression in rat mesangial cells.
The above literatures disclose only compounds which may inhibit the PAI-1 mRNA expression induced by only one of angiotensin II or TGF-.beta..
In the process for investigating compounds capable of inhibiting the PAI-1 mRNA expression, the inventors of the present invention found that, in rat kidney mesangial cells, the PAI-1 mRNA expression induced by a signal from angiotensin II is synergistically increased by an action of TGF-.beta.; that is, the PAI-1 mRNA expression is superinduced by subjecting the rat kidney mesangial cells to a treatment with angiotensin II and TGF-.beta. at the same time, and disclosed the above findings in Japanese Patent Application No. 9-322125, which was laid-open on May 25, 1999 under Japanese Unexamined Patent Publication (Kokai) No. 11-139974. It is surmised that the PAI-1 mRNA expression induced by the simultaneous actions of angiotensin II and TGF-.beta. is closer to the conditions in a living body, in comparison with the expression systems disclosed in the above literatures wherein the PAI-1 mRNA expression is induced by only one of angiotensin II or TGF-.beta..
Further, the present inventors found that genistein compounds or bisindolylmaleimide compounds having specific structures inhibit not only the PAI-1 mRNA superinduction by the simultaneous actions of angiotensin II and TGF-.beta., but also the PAI-1 mRNA induction by one of angiotensin II or TGF-.beta., and disclosed the above findings in Japanese Patent Application No. 9-322125. Therefore, it is expected that the compounds disclosed in Japanese Patent Application No. 9-322125 may inhibit the extracellular matrix accumulation more effectively than the inhibitors disclosed in the above literatures.